The present invention relates to a process for preparing certain substituted caprolactams.
The present invention relates to the area of synthetic methodology and, more particularly, to a process for preparing certain substituted caprolactams.
Marine organisms provide a potential source of biologically active compounds, including compounds which are potentially useful as anti-tumor agents. For example, U.S. Pat. No. 4,831,135 discloses certain bengamide compounds which were isolated by extraction from the Jaspidae marine sponge family native to the waters surrounding the Fiji islands and which exhibit anti-tumor, antibiotic and anthelmintic properties. In fact, the chemistry of Jaspidae sponges has been the subject of numerous publications over the last 10 years.
More recently, WO 00/29382 discloses certain analogs of the bengamides disclosed in the above-mentioned U.S. patent, which analogs are useful in treating various types of tumors. Although WO 00/29382 discloses a suitable process for preparing all of the analogs disclosed therein, their ever-growing importance has resulted in a need for a more practical and commercially acceptable synthesis.
The present invention relates to an improved process for preparing certain substituted caprolactams. The process of the present invention is believed to be more practical and commercially acceptable than the process disclosed in WO 00/29382 since it is carried out under more mild reaction conditions and results in an easier work-up of the desired compounds. More particularly, the process of the instant invention involves the acylation of an aminocaprolactam compound with a lactone compound in the presence of a weak base and a polar, organic solvent, and the hydrolysis of the 1,3-dioxane group of the resulting diamide compound to obtain the desired substituted caprolactam compound.
The present invention relates to an improved process for preparing certain substituted caprolactams of formula I: 
where
R1 is (C1-6)alkyl or (C3-6)cycloalkyl;
R2 is hydrogen or (C1-6)alkyl;
X is (C1-12) alkylene; (C2-12) alkenylene; or (C2-12) alkynylene;
m is 0 or 1; and
R3 is (C3-8)cycloalkyl; or an aromatic ring system selected from II, III, IV and V: 
xe2x80x83where
R4 is hydrogen, chloro, or methoxy;
R5 is hydrogen, chloro, (C1-18)alkyl or (C1-18)alkoxy; and Z is oxygen, sulfur, Nxe2x80x94H, or Nxe2x80x94CH3;
or a pharmaceutically acceptable acid addition salt thereof, where possible. More particularly, the substituted caprolactam compounds of formula I are prepared by a two-step process as depicted below: 
where each R1, R2, X, m and R3 is as defined above.
As to the individual steps, Step A involves the acylation of an aminocaprolactam compound of formula VI, or an acid addition salt thereof, with a lactone compound of formula VII to obtain a diamide compound of formula VIII. The acylation is conducted in the presence of: 1) a weak base, preferably a carboxylate salt such as sodium 2-ethylhexanoate, and 2) a polar, organic solvent, preferably a cyclic ether such as tetrahydrofuran, at a temperature of between 0xc2x0 C. and 50xc2x0 C., preferably at 25xc2x0 C., for a period of between 1 hour and 7 days, preferably for 20 hours.
Step B concerns the hydrolysis of the 1,3-dioxane group common to a diamide compound of formula VIII, to obtain the desired substituted caprolactam compound of formula I. The hydrolysis is typically carried out by dissolving the diamide in a mixture of solvents consisting of 1) a protic acid, preferably an organic acid such as trifluoroacetic acid, or an inorganic acid such as hydrochloric acid; 2) a protic solvent, preferably water, and 3) an inert organic solvent, preferably a cyclic ether such as tetrahydrofuran, at a temperature of between 0xc2x0 C. and 50xc2x0 C. for a period of between 1 hour and 5 hours.
The aminocaprolactam compounds of formula VI and the lactone compounds of formula VII may be prepared as described in WO 00/29382. As indicated above, an acid addition salt of a compound of formula VI may be utilized in Step A. For example, the compound of Example 1g) of WO 00/29382 can be reacted with HCl to form the corresponding hydrochloride salt form of the compound of Example 1h) of WO 00/29382.
Although the diamide compound that is obtained in Step A described above may, if desired, be purified by conventional techniques such as recrystallization, the crude diamide compound is advantageously employed in Step B described above without purification.
The free base of the compound of formula I may, if desired, be converted into the acid addition salt form, where possible. The acid addition salts of the compounds of formula I may be those of pharmaceutically acceptable organic or inorganic acids. Although the preferred acid addition salts are those of hydrochloric and methanesulfonic acid, salts of sulfuric, phosphoric, citric, fumaric, maleic, benzoic, benzenesulfonic, succinic, tartaric, lactic and acetic acid are also contemplated. Such salts may be obtained by reacting the free base of a compound of formula I with the corresponding acid to obtain the desired acid addition salt form.
As is evident to those skilled in the art, the substituted caprolactam compounds of formula I contain asymmetric carbon atoms. It should be understood, therefore, that the individual stereoisomers are contemplated as being included within the scope of the invention.
Preferred substituted caprolactams which may be prepared by the process of this invention are those of formula I where
R1 is (C1-6)alkyl;
R2 is hydrogen or (C1-4)alkyl;
X is (C1-6)alkylene or (C2-6)alkynylene;
m is 0 or 1; and
R3 is (C3-8)cycloalkyl; or an aromatic ring system selected from II, III, IV and V where
R4 is hydrogen, chloro, or methoxy; and
R5 is hydrogen, chloro, (C1-18)alkyl or (C1-18)alkoxy; and Z is oxygen, sulfur, Nxe2x80x94H, or Nxe2x80x94CH3;
or a pharmaceutically acceptable acid addition salt thereof, where possible.
More preferred substituted caprolactams which may be prepared by the process of this invention are those of formula I where
R1 is i-propyl or t-butyl;
R2 is hydrogen or methyl;
m is 0 or 1;
X is (C1-6) alkylene; and
R3 is (C5-7)cycloalkyl; or an aromatic ring system selected from IIa and V: 
where
R4xe2x80x2 is in the meta position and is hydrogen or chloro; and
R5xe2x80x2 is in the para position and is hydrogen, chloro, (C1-18)alkyl or (C1-18)alkoxy;
or a pharmaceutically acceptable acid addition salt thereof, where possible.
Even more preferred substituted caprolactam compounds which may be prepared by the process of this invention are those of formula I where
R1 is i-propyl or t-butyl;
R2 is hydrogen or methyl;
m is 0 or 1;
X is methylene or ethylene; and
R3 is (C5-7)cycloalkyl, phenyl, 3,4-dichlorophenyl, 4-methoxyphenyl, 4-n-decylphenyl, 4-n-decyloxyphenyl or 3-pyridyl;
with the proviso that when m is 0, R3 is (C5-7)cycloalkyl, 4-n-decylphenyl or 4-n-decyloxyphenyl;
or a pharmaceutically acceptable acid addition salt thereof, where possible.
The following examples are for purposes of illustration only and are not intended to limit in any way the scope of the instant invention.